Osteoporotic fractures are a leading cause of disability in older adults, and a major contributor to medical care costs around the world. Prospective studies have found that women with elevated plasma homocysteine have a substantially increased risk of osteoporotic fractures, including hip fractures. The next step is to test whether lowering homocysteine levels will reduce the risk of fractures. We propose to use an ongoing randomized trial to test the hypothesis that reducing plasma homocysteine levels by dietary supplementation with folic acid, vitamin B6, and vitamin B12 will reduce the risk of non- spine fractures in women. The Antioxidant Therapy in Women (Women's Antioxidant Cardiovascular Study [WACS]) Trial, funded by NHLBI, is a randomized, double-blind, placebo-controlled trial of antioxidant vitamins (vitamin C, vitamin E, and beta-carotene) and B vitamins (folic acid, vitamin B6, and vitamin B12) for the prevention of cardiovascular events among female health professionals aged more than or equal to 40 years at enrollment, who had either pre-existing cardiovascular disease (CVD) or greater than or equal to 3 coronary risk factors. Our proposed study, Folic Acid & B Vitamins to Prevent Fractures in Women, will validate and classify fractures that were reported by women in the folic acid/vitamin B6/vitamin B12 arm of WACS. We conservatively project that about 700 non-spine fractures will be validated among 5,442 women during 7.4 years of treatment, providing sufficient power to detect a 19% overall reduction in fracture risk. Utilizing existing archived specimens, we will perform a nested case-cohort study to test whether the effects of treatment with folic acid and B vitamins on risk of non-spine fracture depends on baseline plasma levels of homocysteine, or alternatively by levels of folate or vitamin B12. Studies have found that homocysteine increases the risk of fracture by means besides influencing bone density. Thus, we will use archived plasma to test the hypothesis that treatment with folic acid and B- vitamins influences fracture risk by changing the rate of bone turnover. We will measure change in plasma levels of markers of bone formation (P1NP) and bone resorption (CTX) and explore whether changes in turnover may account for effects of the dietary supplementation on risk of fracture. The proposed study is a cost-effective approach to determining whether a safe and inexpensive nutritional intervention substantially reduces the risk of fracture and to understanding the mechanism of this effect. [unreadable] [unreadable] [unreadable] [unreadable]